Photoinduced copper-catalyzed C–N coupling with trifluoromethylated arenes

Selective defluorinative functionalization of trifluoromethyl group (–CF3) is an attractive synthetic route to the pharmaceutically privileged fluorine-containing moiety. Herein, we report a strategy based on photoexcited copper catalysis to activate the C–F bond of di- or trifluoromethylated arenes for divergent radical C–N coupling with carbazoles and aromatic amines. The use of different ligands can tune the reaction products diversity. A range of substituted, structurally diverse α,α-difluoromethylamines can be obtained from trifluoromethylated arenes via defluorinative C-N coupling with carbazoles, while an interesting double defluorinative C-N coupling is ready for difluoromethylated arenes. Based on this success, a carbazole-centered PNP ligand is designed to be an optimal ligand, enabling a copper-catalyzed C–N coupling for the construction of imidoyl fluorides from aromatic amines through double C-F bond functionalization. Interestingly, a 1,2-difluoroalkylamination strategy of styrenes is also developed, delivering γ,γ-difluoroalkylamines, a bioisostere to β-aminoketones, in synthetically useful yields. The DFT studies reveal an inner-sphere electron transfer mechanism for Cu-catalyzed selective activation of C(sp3)–F bonds.

I am supportive of publication in Nat.Commun.The work expands the scope of monoselective C-F cross-coupling reactions to N-centered nucleophiles.Previous work, published in ACS Catalysis by Xu (ref 35), achieved a similar transformation for phenols and thiols.This present work appears to be a more effective system for anilines and carbazoles, and it also was expanded to a very useful cascade process with styrenes to make betaamino difluorobenzylic compounds.The scope is generally good, although the trifluoromethylarene must be electron deficient.I think this is also important because it shows how metal complexes can be used to promote these very challenging C-F substitution reactions, and it could lead to other photopromoted C-F "cross coupling" methods (whereas most early work on ArCF3 C-F functionalization relied on radical "trapping").I would like the authors to address the points made below before publication.
• Line 47 -explain what you mean by saying "unreactive" • Lline 76 -change the word "remarkably" • Line 82 -in the intro, please note that this chemistry is limited to electron-deficient ArCF3, otherwise I find that this intro paragraph is mostly hype and does not serve to accurately describe the work that is going to be discussed o This should be mentioned in line 127 as well • Line 141 -this description isn't quite right, the key would be the difference between the difluoro and monofluoro variants, since that's where the selectivity difference originates • For the difluoromethylarene scope, please note why only one substrate (bis(difluoromethyl)benzene) is shown o It also seems possible that the double amination process here could be from an ionic mechanism, just forming an iminium ion and having another carbazole add in? • Figure 4 -please draw out L1, it isn't obvious what this ligand is

Reviewer #3 (Remarks to the Author):
The report "Photoinduced Copper-Catalyzed Divergent C-N Coupling with Unreactive Trifluoromethyl Groups" primarily details a copper catalyzed photoredox reaction between electron poor benzotrifluorides and carbazole.The work claims to be selective for single C-F functionalization, but the yields are based on carbozole which is used in five times lower concentration than the fluoride substrates.Despite this, difluoromethyl substrates result in overdefluorination, installing two carbazoles.Further work is performed where i. reaction using only anilines results in C-F substitution followed by H-F elimination to give imidoyl fluorides, and ii.using a combination of styrenes and anilines, an alkene insertion proceeds the reaction with aniline to provide γ-substituted amines.Overall, the work is well performed but very restrictive in its utility given that it is only applicable to very electron deficient benzotrifluorides (used in 5x excess) and carbazole amines.I recommend the work be reevaluated after major revision or submitted elsewhere (if improvement of the scope isn't possible).
Comments for major revisions -The reaction is of little use while restricted to carbazoles.The authors should try extending this work to other secondary amines -Reaction with alkenes/amines (Figure 5) is the most noteworthy work in this report.1991,91,165).Besides, it would be misleading to state that the reaction tolerates EDGs when the authors have attempted to install a meta-position PPh2 (it is actually more EW in the para position due to poor p-p overlap) and when an auxiliary CF3 is still necessary for the reaction.The reported reaction is restricted to very electron deficient benzotrifluorides.-The authors state, "When trifluoromethyl benzene was subjected to this protocol, a moderate yield of the product (3s) was obtained."17% is not a moderate yield.This should be described as poor.Can the authors also specify if yields provided are isolated or GC yields for Figure 2 in the Figure description -Page 1: emerging strategies --> should be 'merging strategies' -"and the combination of transition metal catalysis unlocked new reaction pathways for selective functionalization of C(sp3)-F bond."Add reference 31 to the end of the sentence -In Figure 1, TFFA is a fluorination reagent (it wouldn't be stable under biological conditions).Perhaps the authors could rephrase the description as 'The prevalence of CFn-N unit in biologically and chemically important molecules' -In Figure 1, d: Wok --> Work -Write out methyl tertbutyl ether (MTBE) upon firwst usage.The abbreviation is used before the full name -Gram-scale experiments was --> should be 'were' -"As expected, the reaction was completely prohibited" --> should be 'inhibited' -Add chem draw scheme to Figure 4 for L1 (the molecular structure is hard to discern) -"succesful" --> successful -"it can afford a new route for the synthesis of γ,γ-difluoroalkylamines, which should be esteemed as the bioisostere to β-aminoketones" Please rewrite this sentence.I have no idea what the authors are trying to say.
In this manuscript, the authors realized the selective C-N coupling of C(sp 3 )-F bonds in di/trifluoromethylated arenes via photoexcited copper catalysis, providing an efficient method for the construction of high-value-added fluorinated compounds.A wide range of ArCF 3 with diverse functional groups can participate in the defluorinative C-N coupling with various carbazoles and arylamines through the use of different ligands.Moreover, a variety of -difluoroalkylamines can be obtained via a 1,2-difluoroalkylamination process of styrenes, which further demonstrated the synthetic application of this strategy.The DFT studies revealed an inner-sphere electron transfer process between [L1Cu I ]* and ArCF 3 .The manuscript can be published in Nature Communications after minor revisions.
1.In this work, only aryl substituted trifluoromethyl compounds, which are unactivated substrates in Figure 2, can be tolerated in this strategy.Therefore, the description of "unreactive trifluoromethyl groups" in the title and text should be modified.
2. In 2021, the Yu group has realized the visible-light photoredox-catalyzed radical defluorocarboxylation of C(sp 3 )-F bonds with CO 2 (Chem 2021, 7, 3099-3113), which should also be presented in the background Introduction and Figure 1b.
3. On page 4, the yield corresponding to CuCl is not consistent with the yield shown in Table 2.Pplease double check the manuscript carefully.
4. The mass balance in the reactions has not been discussed.What kinds of by-products are formed in the reaction optimization process or scope studies? 5.Although a range of primary arylamines are suitable for the reaction, it will be interesting to know what happened with N-methylaniline.Whether the C-N coupling happened with N-methylaniline? 6.In Figure 5, for the substrate scope of amines, have the authors tried other nitrogen nucleophiles instead of aromatic amines, such as nitrogen-containing heterocycles or hydrazines? 7. A related review (Sci.China Chem.2021, 64, 1630-1659) should also be cited.

Point-by-point response to reviewers
Reviewer #1 (Remarks to the Author): In this manuscript, the authors realized the selective C-N coupling of C(sp 3 )-F bonds in di/trifluoromethylated arenes via photoexcited copper catalysis, providing an efficient method for the construction of high-value-added fluorinated compounds.A wide range of ArCF3 with diverse functional groups can participate in the defluorinative C-N coupling with various carbazoles and arylamines through the use of different ligands.Moreover, a variety of difluoroalkylamines can be obtained via a 1,2-difluoroalkylamination process of styrenes, which further demonstrated the synthetic application of this strategy.
The DFT studies revealed an inner-sphere electron transfer process between [L1Cu I ]* and ArCF3.The manuscript can be published in Nature Communications after minor revisions.

Thank you very much for your positive evaluation to the synthetic values of our new synthetic methodology. Much appreciated!
The following points need to address before the publications 1.In this work, only aryl substituted trifluoromethyl compounds, which are unactivated substrates in Figure 2, can be tolerated in this strategy.Therefore, the description of "unreactive trifluoromethyl groups" in the title and text should be modified.Change in Figure 1b:
3. On page 4, the yield corresponding to CuCl is not consistent with the yield shown in Table 2. Please double check the manuscript carefully.
Answer: Thank you for your attention to detail.Upon re-examination, we confirm that the GC yield of 3a was 72% when CuCl served as the catalyst.
4. The mass balance in the reactions has not been discussed.What kinds of byproducts are formed in the reaction optimization process or scope studies?
Answer: Thanks for your valuable suggestion.The major by-product was the dimer of the corresponding difluorobenzylic radical, but its yield typically remained below 5%.According to your suggestion, one new sentence was added in the revised Supplementary Information as" Although the dimmer of the corresponding difluorobenzylic radical could be detected as the major byproduct, its yield typically remained below 5%".
As to the 1,2-difluoroalkylamination reaction shown in Figure 5, the major byproduct was the corresponding imidoyl fluoride and its yield in the reaction optimization process was shown in the revised Supplementary Table 16.

Thank you very much for your positive evaluation to the synthetic values of our new synthetic methodology. Much appreciated!
I would like the authors to address the points made below before publication.

 Line 47 -explain what you mean by saying "unreactive"
Answer: Since the C(sp 3 )−F bond in CF3 was one of the strongest single bonds to carbon (BDE>80 kcal mol -1 ), it was rather inert under common reaction conditions.According to your suggestion, we have made the corresponding changes as "(1) the bond dissociation energy (BDE) of C-F bond in CF3 is strong 46 but the BDE of the remaining C-F bonds significantly decreases once the F atoms have been substituted.".
 Line 76 -change the word "remarkably" Answer: Thanks for your advice.We have changed "remarkably" in the revised manuscript to "In addition".
 Line 82 -in the intro, please note that this chemistry is limited to electrondeficient ArCF3, otherwise I find that this intro paragraph is mostly hype and does not serve to accurately describe the work that is going to be discussed； benzotrifluorides were subjected to this protocol, the product (3s) could only be obtained in 17% isolated yield".
 Line 141 -this description isn't quite right, the key would be the difference between the difluoro and monofluoro variants, since that's where the selectivity difference originates Answer: Thank you very much for your helpful suggestions.According to your suggestion, we have adjusted the description as "Because the difference between the difluoro-and monofluoro-variants, double defluorinative C-N coupling processes could take place for difluoromethylated arenes"  For the difluoromethylarene scope, please note why only one substrate (bis(difluoromethyl)benzene) is shown；It also seems possible that the double amination process here could be from an ionic mechanism, just forming an iminium ion and having another carbazole add in?
Answer: Thanks for your reminder.Considering that there are more commercially available trifluoromethylated arenes than difluoromethylated ones and the compound with remaining fluorine atoms may be of more synthetic use, we didn't try that a lot of difluoromethylarenes.The formation of the corresponding iminium ion is also rational and could not be ruled out.

:
Thank you very much for your important suggestions.According to your suggestion, the title has been changed to "Photoinduced Copper-Catalyzed Divergent C-N Coupling with Trifluoromethylated Arenes"; the description in the Introduction has been changed to "This protocol offers a divergent C-N coupling for the synthesis of synthetically interesting -difluoromethylamines, imidoyl fluorides and -difluoroalkylamines from electron-deficient trifluoromethylated arenes and aromatic amines"; the description in the Conclusion has been modified as "In summary, we have developed a divergent defluorinative C-N coupling reaction of electron-deficient di-and trifluoromethylated arenes and aromatic amines via photoexcited copper catalysis".2. In 2021, the Yu group has realized the visible-light photoredox-catalyzed radical defluorocarboxylation of C(sp 3 )-F bonds with CO2 (Chem 2021, 7, 3099-3113), which should also be presented in the background Introduction and Figure 1b.Answer: Thanks for your suggestion.We have added the literature (Chem 2021, 7, 3099-3113) in the background Introduction and Figure 1b.
2 h.[b] GC yield with dodecane as internal standard.[c] Isolated yield. 5.Although a range of primary arylamines are suitable for the reaction, it will be interesting to know what happened with N-methylaniline.Whether the C-N coupling happened with N-methylaniline?Answer: Thank you very much for your important suggestions.When Nmethylaniline was employed as the N nucleophile, the desired defluorinative C-N coupling product could be detected with ~ 5% yield by GC-MS.However, despite our efforts, we were unable to further improve its yield.GC-MS spectra was shown as following: 6.In Figure 5, for the substrate scope of amines, have the authors tried other nitrogen nucleophiles instead of aromatic amines, such as nitrogen-containing heterocycles or hydrazines?Answer: Thank you very much for your thoughtful suggestions.We have explored the use of nitrogen-containing heterocycles such as pyrroles and imidazoles.Unfortunately, they failed to give the desired products.On a positive note, we found that phenylhydrazine was suitable for the desired 1,2difluoroalkylamination, and we have incorporated the corresponding product into Figure 5 as 11r.7. A related review (Sci.China Chem.2021, 64, 1630-1659) should also be cited.Answer: Thank you very much for your helpful comments.We have added the literature in the revised manuscript.19.Ai, H.-J., Ma, X., Song, Q. & Wu, X.-F.C-F bond activation under transitionmetal-free conditions.Sci.China Chem.64, 1630-1659 (2021).Reviewer #2 (Remarks to the Author): The authors report a photopromoted Cu-catalyzed defluoroamination coupling protocol for electron-deficient trifluoromethylarenes.Carbozoles react using simple Cu/phosphine conditions to provide difluorobenzylic amine products in good yields.Mechanistic studies support a SET pathway from the LCu-carbazole intermediate to generate a difluorobenzylic radical intermediate for amination.The authors used this insight to develop a new ligand system that allowed anilines to do double C-F substitution en route to imidoyl fluorides and for a cascade addition sequence with styrenes.Computational studies support an inner sphere ET pathway for this process.I am supportive of publication in Nat.Commun.The work expands the scope of monoselective C-F cross-coupling reactions to N-centered nucleophiles.
This should be mentioned in line 127 as well Answer: Thanks for your thoughtful suggestions.According to your suggestion, we have made the following changes as "This protocol offers a divergent Cfluorides and -difluoroalkylamines from electron-deficient trifluoromethylated arenes and aromatic amines.The broad reaction scope, excellent functional group tolerance and gram-scale ability enable this strategy promising for the construction of value-added products"in the line 82.In line 127, we have reorganized the sentence as "When